A new research from VHIR links the mtDNA levels with the risk of parkinsonism in patients with spastic paraplegia

Dr. Josep Gámez, head of the Peripheral Nervous System group of the Vall d’Hebron Research Institute (VHIR) and coordinator of the CSUR Rare Neuromuscular Diseases, the CSUR of Ataxias and Hereditary Paraplegias, and member of the European Reference Network for Rare Neuromuscular Diseases (EURO-NMD) from Vall d’Hebron Hospital, has participated in a study that associates mutations in the SPG7 gene, related to spastic paraplegia type 7, with parkinsonism symptoms, pointing out a probable relation between the mitochondrial dysfunction caused by mutations in this gene with early onset Parkinson’s disease (EOPD). The study is published in the magazine Movement Disorders.

Spastic paraplegia type 7 is an autosomal recessive hereditary adult-onset disease, that ranges from its less severe symptoms, like spasticity and weakness on the lower limbs, to complex conditions such as ataxia, optic atrophy, intellectual disability, deafness, dementia, peripheral neuropathy and epilepsy. Mutations in the SPG7 gene are known to be responsible of this disease, but in addition, SPG7 gene alterations cause cerebellar ataxia in the adulthood and sometimes EOPD, Parkinson’s disease cases that appear before the 40 or 50 years of age.

This gene codifies for a mitochondrial protein called paraplegin, which could explain the similarities of severe spastic paraplegia cases with mitochondrial diseases. Although the relationship between the mutation and the mitochondrial dysfunction is still to be determined, patients with a defective paraplegin can bear alterations in the mitochondrial DNA (mtDNA) levels.

The study was based on the symptom characterization of 35 patients from Spain, 8 of which from Vall d’Hebron, and analyzed the genetic alterations in the SPG7 gene and the mtDNA levels in the clinical context of each patient.

Results indicate that the mutation c.1529C>T (pAla510Val) in homozygosis is the most frequent alteration in this patient cohort, being present in the 45,7% of the cases. However, it has not been possible to link the severity of the clinical manifestations to the presence of the mutation, as patients with only one copy of the gene mutated had more severe conditions that individuals with both copies affected. Remarkably, parkinsonism symptoms were found in 7 of the patients studied, suggesting an association between EOPD and alterations in the SPG7 gene.

Furthermore, individuals with the most prominent features of mitochondrial disease were the ones who presented the highest levels of mtDNA in peripheral blood, and vice versa, stablishing the mtDNA determination as an interesting biomarker for predicting the parkinsonism symptoms in families carrying this mutation. The relevance of the mtDNA as a biomarker reinforces the idea that a glimpse of the neurodegeneration status can be obtained from tissues other than the brain; in this case, from measuring the mtDNA levels in blood.